The use of sterile packed hemofiltration substitute solutions represents the largest single cost factor in continuous diafiltration treatment processes. While recent data suggests an improved outcome with higher diafiltrate flow, this might increase process costs.
Specific terms used in the description of the present invention are defined below:
Complex biological fluid compartment (A) is comprised of one or more communicating fluid compartments. Concentrations of chemicals or biochemicals are influenced by formation, distribution, transformation and elimination. Those processes can vary between a biochemical X or Y.
An example of a complex biological fluid compartment are bioreactors with active components, for example liver cells that transform or metabolize toxins. In this case, the reactor medium fluid chamber would be one compartment and the interior of the liver cells a second compartment, both communicating via the cell membrane. Enzymatic processes inside the cell, and transport processes of substances through the cell membrane will affect concentrations of the substances in the reactor medium fluid chamber. Another example of a complex biological fluid compartment (A) is mammal, such as human, blood.
Membrane dialysis/filtration: a combined procedure for monitoring the concentration of substances in a complex biological fluid compartment (A). It is conducted by conducting fluid (A), which is filled with undesired substances along a flow path including a porous membrane which separates (A) from a rinsing side (B) which contains a rinsing fluid and does NOT contain the undesired substances. In the case of dialysis, if the molecular size of the undesired substances are small enough to pass through the pores of the porous membrane then the undesired substances will follow the concentration gradient from (A) to (B), thereby passing to the rinsing side. This process can be supported by a convective transport. In this case, a liquid flow (crossflow) from A to B is applied by a pressure gradient. The substances are then also transported by convection through the membrane, wherein the fluid leaving compartment (A) by filtration (i.e., the filtrate) can be replaced completely or in part by a substitution solution, i.e., substitution fluid (substitute). A combination of dialysis and filtration can occur but in extreme cases can also be applied as only filtration or only dialysis.
Rinsing compartment (B): the compartment that is separated from the complex biological fluid compartment (A) by a separating device, which can be a membrane. rinsing compartment (B) is filled with dialysate, filtrate, or both.
Dialysate is the fluid described above in the definition of “membrane dialysis/filtration”, present in in the rinsing compartment (B) and can take up the undesired substances by concentration gradient.
Substitute fluid is the fluid described above in the definition of “membrane dialysis/filtration” which is supplied to compartment (A) as replacement fluid in a filtration process.
Diafiltrate is the fluid described above in the definition of “membrane dialysis/filtration” that is present in the rinsing compartment (B) that has absorbed undesired molecules by diffusion and or convection in the process of cleaning the fluid on the (A) side and is thus enriched with undesired molecules.
Net throughput of dialysate/substitute fluid: the diafiltrate that is removed from the process after a single passage along the membrane filter, thereby not entering the cleaning regeneration cycle (RGC) that is re-supplied to the diafiltrate.
The regeneration cycle (RGC): The regeneration cycle is a device that removes the hereinafter described substance Y out of the diafiltrate, but not the hereinafter described substance X, by means of filtration, adsorption, or biological treatment processes.
Substance group X: one or a plurality of disease-causing substances (undesired molecules), which cannot be eliminated directly by the regeneration cycle (RGC) because known technologies do not provide retention or adsorption capacity for a substance from substance group X. A substance from substance group X can pass the separating device/membrane from (A) to (B) by dialysis or filtration due to pore size and molecular weight range.
Substance X: one or a plurality of substances from substance group X.
Substance group Y: one or a plurality of substances that can be depleted by the regeneration cycle (RGC), because it has retention/adsorption capacity for Y.
Substance Y: one or a plurality of substances from substance group Y.
The cleaning procedure of complex biological fluid compartments systems such as bioreactor fluids or blood by membrane dialysis/filtration today often involves unnecessarily high consumption of dialysate or substitute fluid, as their flow rate needs to be adjusted/increased to the point that the concentration of fast generated undesired toxins can be controlled.
In complex biological fluid compartments, such as in bioreactors for the cultivation of liver cells, this may for example be urea, formed by the Krebs cycle. Urea could be removed from the reactor medium by diafiltration. Also urea accumulates in the bloodstream of patients with kidney damage.
Particularly in the critical care applications of diafiltration, this leads to an often unnecessary consumption of cost intensive sterile prepackaged dialysate and substitute solutions.
Treatment time is adjusted according to the removal of the undesired substance under a given dialysate/filtrate flow. If the removal rate is low due to low flow rates, treatment time must be extended. This may result in prolonged anticoagulation (eg, heparin or citrate), which can have side effects) (e.g., bleeding or alkalosis and hypernatremia).
Extracorporeal blood purification by diafiltration is based on the diffusive (dialysis) and/or convective (diafiltration) transport of permeable molecules from the blood or plasma through a porous membrane into a rinsing solution compartment.
In the case of dialysis and filtration, the rinsing solution should be free of unwanted and undesired substances or toxins. The rinsing solution would be used as a substitute fluid during filtration or as a dialysate in case of dialysis. On the other hand, valuable substances should not be transferred from the biological fluid to the dialysate or filtrate. For example, in the case of blood, glucose is a valuable component that should not be transferred, which can be achieved by maintaining the valuable components at the same concentration in the rinsing solution. In this widely used approach, dialysis fluids are usually mixed from concentrates and reverse osmosis water lines. It needs a complex technology (water treatment systems, dialysis machines). Because of the high technological complexity, trained technicians and dialysis nurses knowledgeable in the logistics of water flow are needed.
Alternative known prior art includes systems with a closed dialysate circuit without continuous flow of dialysate and/or substitute fluid.
In the BioLogic DT system a small closed dialysate reservoir is recycled. The reservoir is regenerated by a suspension of ion exchange resins and a relatively fine-pored charcoal. It is used with no steady dialysate flow which makes for the depletion of dialyzable, but non-absorbed substances. Although the system saves the dialysate, it has not been particularly useful for monitoring the urea and ammonia levels.
In the REDY system, a small closed set dialysate reservoir is regenerated in a recirculation system. The reservoir is regenerated through a complex process that includes charcoal but also requires the decomposition of urea in toxic ammonia by an enzyme (urease) which is secondarily adsorbed chemically by zirconium phosphate.
Because the system saves dialysate due to production of ammonia by the urease it makes an effective removal of ammonia from the patient's blood impossible.
Also, no continuous dialysate flow is used, which would allow the depletion of non adsorbed unwanted substances from blood. It should be noted that many of the undesirable substances in complex biological fluids are not yet known.
In the REDY system, where there is a 100 percent recovery of dialysate or substitute, there is a risk of accumulation of unwanted non-adsorbed substances in the regeneration cycle which compromises the effective cleaning process by dialysis.
In the Genius System, a large volume dialysate reservoir is used. Detoxification utilizes an extremely high volume of dialysate (up to 80 liters). No adsorbents are used. If the concentration is increased in the dialysate to the blood level the system stops working and must be changed.
Combined dialysis and adsorption (e.g. by Renaltech are presented in series and in direct contact with blood, and therefore are less biocompatible and the two mechanisms are not independently adjustable. These adsorbents in direct contact with blood are used to remove non dialyzable substances by adsorption from the blood.
Methods in which adsorbents are used in conjunction with a plasmapheresis filter (plasmapheresis, Prometheus) allow, usually no high trans membrane flows and include risk of loss of important proteins or other valuable materials to the adsorbents.
The MARS procedure (EP 0615780 B1) combines the removal of water-soluble and protein-bound substances. Its uniqueness is that the biological compartment (A), mostly blood, passes through a protein impermeable (blood) side of an asymmetric dialysis membrane, which is coated with proteins that have a bond with toxins with high protein, affinity. On the opposite side of the Dialyzer there is dialysis fluid that contains a dissolved protein with binding capacity for protein bound toxins. Those proteins enter the dialysis membrane fiber which has larger pores on the outside, allowing those proteins entering and diffusing close to the inner side where smaller pores prevent them from entering the blood. This enables passage of albumin bound and small water soluble molecules.
Since these proteins are expensive, the protein-containing dialysate is regenerated by sequential dialysis, followed by serial adsorption by two sorbents. The effect is that albumin bound toxins are finally bound by the sorbents. A differentiated regeneration of the dialysate in the interest of saving the dialysate does not occur. On the contrary, dialysis efficacy is reduced by applying a secondary dialyzer circuit to remove diffusible substances. In published clinical trials (Heemann et al. Hepatology 2002) supporting clinical efficacy, dialysate flow rates of 500 ml/min had been applied in the secondary dialysate circuit.